1. Field of the Invention
The present invention relates to a device for sealing a vessel, in particular a cartridge or a test-tube for accommodating a freeze-dried pharmaceutical product, wherein the vessel comprises at its opening end an opening edge and an adjoining longitudinal portion with an evenly formed inner cross section, including a front plunger to be positioned inside the vessel at the longitudinal portion.
Furthermore, the present invention relates to a method of manufacturing a sealed vessel, in particular a cartridge or a test-tube, containing a freeze-dried pharmaceutical product, wherein the vessel comprises at its opening end an opening edge and an adjoining longitudinal portion with an evenly formed inner cross section, at least comprising:
a drug solution provisioning step in which a drug solution to be freeze-dried is inserted into the vessel;
a drug solution sealing step in which the drug solution is sealed together with internal air by positioning a front plunger inside the vessel at the longitudinal portion; and
a freeze-drying step in which the drug solution is freeze-dried so as to form the freeze-dried pharmaceutical product.
This application is a U.S. National Stage entry of International Application No. PCT/EP2011/063582, entitled “Device for Sealing a Vessel and Method of Manufacturing a Sealed Vessel”, filed on Aug. 8, 2011, which claims the benefit of priority to Japanese Patent Application No. 2010-178974, filed Aug. 9, 2010, the contents of each of which are incorporated herein by reference in their entirety herein.
2. Description of Related Art
Many substances, in particular in the medical, pharmaceutical and chemical field like for instance pharmaceutical products or medically and/or biologically active substances, are sealed in vessels for storage purposes. Typically, they require careful sealing in order to preserve their stability and their specific characteristics over a given time period. Moreover, many of these substances are extremely expensive, and many of them also require careful handling when they are being administered. Examples for the substances in question include, for instance, injection drugs that have been newly developed in recent years for treating or preventing intractable diseases, in addition to cancer controlling drugs, cancer inhibiting drugs and the like.
As mentioned above, in many of these substances, the stability of their medicinal efficacy during storage is critical. Accordingly, in many cases a method is employed in which, in order for the pharmaceutical ingredient in the substance, e.g. a drug, to be preserved both safely and stably over a long period, a freeze-dried pharmaceutical product is prepared by freeze-drying the drug with the pharmaceutical ingredient so as to change it into powder form. When the freeze-dried pharmaceutical product is to be used, it is dissolved or suspended in a diluent or suspension (generically referred hereinafter simply as ‘a diluent’) so as to prepare an injection drug which is then administered to a patient.
Vessels employed in prior art for the above-mentioned purposes, once they are closed by means of a stopper or a plunger, are steadily sealed up to the moment when the vessel is opened for the purpose of using the sealed substance, e.g. in order to administer it to a human patient. As a consequence, during storage of the substance in the sealed vessel it is almost impossible to manipulate the sealed substance in any way, e.g. by releasing gas from the inside of the vessel, by freeze-drying the substance, by dissolving it in a diluent, by preparing it for administration to a patient, or the like. In order to carry out such manipulation the vessel has to be opened by completely releasing the stopper or plunger from the vessel. However, such procedure is not only extremely elaborate and time-consuming, but also comes along with various problems, for instance sterility problems or simply that the stopper or plunger gets lost during the substance manipulation procedure.
Hereinafter, the problems as outlined above are described in more detail with respect to the specific exemplary situation of industrially manufacturing dual chamber combined contained-cartridges and syringes including a freeze-dried pharmaceutical product. In prior art, in order to change an injection drug with a pharmaceutical ingredient into a freeze-dried pharmaceutical product, vials are filled with an injection drug in a liquid solution state, namely, with an injection drug solution, and freeze-drying processing is then performed on the individual vials in a low-temperature vacuum apparatus. As a result of this processing, the injection drug is changed into a freeze-dried pharmaceutical product, and the freeze-dried pharmaceutical product can be preserved by sealing the vials with rubber plungers and aluminum caps. When an injection drug is to be administered to a patient, a diluent that has been aseptically loaded into a separate container from that holding the freeze-dried pharmaceutical product is suctioned into an empty syringe. The injection needle of this syringe is then pushed through the rubber plunger of the vial and the diluent is injected into the vial. The freeze-dried pharmaceutical product is then dissolved or suspended inside the vial so as to create an injection drug. Preparations to enable the injection drug to be administered to a patient are completed by then suctioning this injection drug back into the syringe.
In this manner, because the task of suctioning a diluent from a container into a syringe, the task of injecting the diluent from this syringe into a vial in which a freeze-dried pharmaceutical product has been sealed, and the task of once again suctioning the injection drug prepared inside the vial back into the syringe must be performed in sequential stages, a considerable amount of labor and time are required. In addition, there is a possibility of the injection drug and injection equipment becoming contaminated with bacteria, foreign substances and the like while the injection drug is being transferred.
In order to solve such problems, dual chamber combined container-syringes have been developed (see, for example, Japanese Examined Patent Application, Second Publication No. H4-46152). In this dual chamber combined container-syringe, a front plunger is inserted into the distal end side of a cartridge, and a middle plunger is inserted into a central portion inside the cartridge so that the interior of the cartridge is divided into a front chamber and a rear chamber by the middle plunger. A bypass portion is formed in a portion of the cartridge on the distal end side of the middle plunger by expanding the diameter in the portion of the inner circumference of the cartridge. The front chamber, which is on the distal end side of the middle plunger, is filled with a freeze-dried pharmaceutical product which is then sealed therein, while the rear chamber, which is on the base end side of the middle plunger, is filled with diluent. The diluent inside the rear chamber is sealed therein by an end plunger that is inserted into the rearmost side of the cartridge interior.
When this dual chamber combined container-syringe is put to use, an injection needle is mounted onto a front assembly provided on the distal end side of the cartridge, and a plunger rod is inserted from the rear end side of the cartridge and is screwed into the end plunger so as to become fixed thereto. If the end plunger is pushed in using the plunger rod, the diluent which was sealed between the end plunger and the middle plunger moves forward together with these two plungers. When the middle plunger enters into the bypass portion of the cartridge, because the bypass portion has an expanded diameter, the sealing of the diluent by the middle plunger is released. As a result, the diluent passes through the bypass portion and enters into the front chamber which has been filled with the freeze-dried pharmaceutical product. The freeze-dried pharmaceutical product is dissolved by the diluent, and the injection drug to be administered to a patient is completed.
According to this dual chamber combined container-syringe, it is possible to perform the task of mixing together a freeze-dried pharmaceutical product and a diluent inside the cartridge by the simple action of pushing in the plunger rod. Accordingly, the operation is extremely convenient. Moreover, because the mixing action takes place inside the syringe, the injection drug does not come into contact with the outside air and any contamination of the injection drug by bacteria or foreign substances can be avoided.
The task of filling the interior of a cartridge with a freeze-dried pharmaceutical product in a dual chamber combined container-syringe is performed after, for example, the quantities of freeze-dried pharmaceutical products needing to be administered have been weighed. However, because the freeze-dried pharmaceutical product is in a powder form, the problem arises that, compared with liquids, precise quantities are difficult to measure. Because such freeze-dried pharmaceutical product is administered to human patients, it is necessary for accurate volumes thereof to be loaded into syringes.
A method in which freeze-drying processing is performed on each individual cartridge for liquid injection drugs (hereinafter, referred to as injection drug solutions) loaded into cartridges may also be considered. In this case, during the freeze-drying processing, it is necessary for the inside and outside of the cartridges to be in open communication with each other so that the injection drug solution is exposed to the atmosphere outside the cartridge. However, at times other than during freeze-drying processing, in order to secure the sterility of the cartridge interior, it has been necessary to place the interior of the cartridge in a sealed state and avoid the injection drug solution or freeze-dried pharmaceutical product coming into contact with the outside atmosphere.
Because several tens of hours are required to perform a single freeze-drying step, from the standpoint of work efficiency, it is preferable for freeze-drying to be performed simultaneously on a large quantity of cartridges.
In this case, because a certain length of time is needed until a predetermined number of cartridges containing injection drug solution are accumulated, it is not possible for the task of loading injection drug solution into a cartridge and the task of freeze-drying the injection drug solution to be performed without an intervening delay. Accordingly, it is necessary for cartridges loaded with an injection drug to have a sufficiently high level of sealability to allow them to be stored for a certain length of time. However, conventionally, no technology exists that, after a cartridge has been loaded with an injection drug and placed in a sealed state, enables the inside and outside of the cartridge to be in open communication with each other only during the freeze-drying processing. Accordingly, the problem has existed that it has not been possible to manufacture highly sterile dual chamber combined container-syringes at a superior level of productivity.
The present invention was devised in view of the above circumstances, and has an object to provide a device for sealing a vessel and a method of manufacturing a sealed vessel that ensures high levels of productivity and sterility of the sealed substances, and that enables the vessels to be filled with accurate quantities of freeze-dried pharmaceutical products.